Computer simulation of free energies to predict cis/trans equilibria of prolyl peptides and solvation free energies of phenylalanyl peptides

Two computer simulation studies were performed; one to help understand the structure-function relationships of prolyl peptides (Part I) and the other to help predict more efficient pharmaceutical drug delivery by molecular modification of small peptides (Part II). In Part I, the free energy perturbation (FEP) method, using AMBER, was utilized to calculate the Gibbs free energy difference between <i>cis</i> and <i>trans</i> conformers of Ace-Tyr-Pro- NMe and Ace-Asn-Pro-NMe, from which the ratio of <i>cis</i> to <i>trans</i> conformers was obtained. Our simulation generated much lower <i>%cis</i> for both peptides as compared with experimental values and possible problems in our computational schemes are presented. However, our results were encouraging in that they predicted preference of <i>trans</i> conformers for both peptides and higher <i>%cis</i> for Ace-Tyr-Pro-NMe, compared to Ace-Asn-Pro-NMe, which agrees with experimental results. Part II applied semi empirical (AMS0L) and microscopic simulation (POLARIS) methods to obtain the solvation free energies of a series of phenylalanyl peptides with various degrees of methylation on their backbone nitrogens. It was clearly predicted that as a peptide length increased, so solvation free energy decreased, indicating less favorable permeability through the cell membrane system, in agreement with data in the literature. AMSOL also showed that solvation free energy change upon methylation was variable depending on the position of the substituted backbone nitrogen, which disagrees with the literature. However, non-systematic solvation free energy change of small amines upon methylation was successfully predicted by AMSOL, in good accord with experimental data.

Name thesis:degree_name

Master of Science

Level thesis:degree_level

masters

Discipline thesis:degree_discipline

Biochemistry

Department dc:contributor.department

Biochemistry

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

1996

Author dc:creator

• Kurusu, Tamaki

Chair dc:contributor.committeechair

• Bevan, David R.

Committee members dc:contributor.committeemember

• Newton, William E.
• Gregory, Eugene M.

• Molecular Modeling
• Simulation
• Free Energy
• Proline
• Solvation

Statement dc:rights

• In Copyright

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Language dc:language.iso

en

Dc Identifier Other

etd-10072005-094901

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/45091